Atrial thrombus caused by atrial fibrillation and thrombi formed by the disruption of atheroma (atherosclerotic vessels) in the aorta or carotid artery may cause ischemic cerebrovascular diseases such as cerebral embolism, cerebral infarction, transient ischemic attack, etc., and ischemic heart diseases such as angina pectoris, myocardial infarction, atrial thrombus caused by atrial fibrillation, cardiac insufficiency, etc. While blood circulation must have good fluidity to deliver oxygen and nutrients to body tissues and remove waste (from the circulatory system), it is required to be coagulative to stop bleeding for the prevention of blood loss due to injury. When the balance between such opposed functions of fluidity and coagulation is lost and shifts to coagulation, an intravascular thrombus is formed, which is thought to cause ischemic cerebrovascular disorders and heart diseases.
The fibrinolytic system plays important roles in thrombolysis, tissue destruction and repair, cell migration, etc. The fibrinolytic system is activated when plasminogen activator (hereinafter referred to as “PA”) converts plasminogen to plasmin, whereas plasminogen activator inhibitor-1 (PAI-1) inhibits PA.
Tissue plasminogen activator (hereinafter referred to as “t-PA”) converts plasminogen, i.e., the precursor of plasmin, to plasmin. Plasmin converts fibrin to a fibrin degradation product by breaking it down.
PAI-1 is a serine protease inhibitor that specifically inhibits t-PA and urokinase plasminogen activator (hereinafter referred to as “u-PA”), suppresses plasmin generation, and as a result inhibits fibrin degradation.
Based on tertiary structural differences, PAI-1 is present in an active form that shows PA inhibitory activity and in a latent form that shows no PA inhibitory activity.
In plasma, PAI-1 is known to be typically present in a concentration of 20 ng/mL, and produced in hepatocytes, megakaryocytes and lipocytes in addition to the vascular endothelial cells, which are the primary PAI-1 producing cells.
PAI-1 is an acute phase protein, and is thought to be one of the factors that cause ischemic organ dysfunctions in sepsis and disseminated intravascular coagulation syndrome (DIC) through accelerated production due to various cytokines and growth factors. Further, genetic polymorphism due to single base substitutions in the PAI-1 gene promoter is known, and it has been revealed that plasma PAI-1 concentration increases as a result of such genetic polymorphism.
Furthermore, in diabetes mellitus, accelerating arteriosclerosis and microvascular complications are presumed to be factors in ischemic heart disease, diabetic retinopathy, and renal damage, i.e., all are critical complications of diabetes mellitus. For example, in diabetic nephropathy, increased extracellular matrix in the glomerulus and fibrous stroma are observed characteristics, and PAI-1 expression is increased in the glomerulus and renal tubules. In proximal renal tubule incubation, increased PAI-1 production is evident under hyperglycemic conditions. Further, a correlation between PAI-1 expression in renal tissues and macrophage infiltration is confirmed in experiments using a model mouse with renal interstitial fibrosis (see Non-Patent Documents 1 and 2).
Furthermore, PAI-1 concentrations in urine are documented as being high in nephrotic syndrome patients based on the measurement results of PAI-1 levels in urine collected over a 24-hour period from nephrotic syndrome patients (see Non-Patent Document 3).
As described above, deep involvement of PAI-1 in kidney diseases such as diabetic nephropathy, chronic kidney disease (CKD), nephrotic syndrome, post-renal kidney injury, and pyelonephritis has been extensively studied and reported (see Non-Patent Documents 4 to 8). In contrast thereto, as a result of administrating an inactive PAI-1 mutant or t-PA as a PAI-1 antagonist to a Thy-1 nephritis model, it is reported that the alleviation of inflammation (cellular infiltration), TGF-β suppression, and a decrease in mesangial matrix are observed, whereby Thy-1 nephritis is alleviated (Non-Patent Documents 9 and 10).
Reduced fibrinolytic activity due to an increased PAI-1 concentration in plasma is associated with ischemic heart diseases such as angina pectoris, myocardial infarction, cardiac insufficiency; deep-vein thrombosis and pulmonary embolism originated therefrom; and diabetic angiopathy (for example, see Non-Patent Document 11). In addition to reduced fibrinolytic activity, some other thrombogenic abnormalities including hypercoagulation and platelet hyper-aggregation are also seen in diabetic patients. They are caused by microthrombus formation, and play important roles in the progression of diabetic microangiopathy and diabetic macroangiopathy.
As described above, PAI-1 is presumably involved in the formation and progression of various pathological conditions of various diseases, specifically, various kinds of thrombosis, cancer, diabetes mellitus, ocular diseases such as glaucoma and retinopathy, polycystic ovary syndrome, radiation damage, alopecia (calvities), splenohepatomegaly, arteriosclerosis, etc. (see Non-Patent Documents 12 to 17). In addition, PAI-1 is also presumably involved in control of the circadian rhythm, which is presumed to be involved in the formation of vascular endothelial cells and the occurrence of events such as cerebral infarction and myocardial infarction (Non-Patent Documents 18 to 20). For this reason, a compound that inhibits PAI-1 activity is useful as a preventive and treatment agent for various diseases such as thrombosis, cancer, diabetes mellitus, diabetic complications, various kidney diseases, ocular diseases such as glaucoma and retinopathy, polycystic ovary syndrome, alopecia, bone-marrow regeneration, splenomegaly due to extramedullary hematopoiesis, amyloidosis, and arteriosclerosis (see Non-Patent Documents 21 and 22). In particular, Non-Patent Document 14 reports that PAI-1 promotes angiogenesis in the retina, and a PAI-1 inhibitor is therefore considered to be useful as an agent for preventing and treating retinopathy and various other diseases that occur in association with angiogenesis. Further, Non-Patent Document 23 states that a low-molecular-weight PAI-1 inhibitor inhibits differentiation of adipose cells, thereby inhibiting the development of diet-induced obesity. Therefore, a PAI-1 inhibitor is presumably effective for preventing and treating obesity.
Tissue fibril formation occurs in many tissues and organs such as the lungs, heart, blood vessels, liver, kidneys, etc. A report has disclosed that the progression of pulmonary fibrosis can be suppressed by the administration of a PA or PAI-1 inhibitor to activate the fibrinolysis system (Non-Patent Document 24). Therefore, a PAI-1 inhibitor is known to be effective for treating tissue fibrosis, in particular pulmonary fibrosis (Non-Patent Documents 22, 25, and 26). However, there is no drug available to treat them radically. In reality, adrenocorticotropic hormones such as predonisolone, corticosteroid, etc., and cytotoxic drugs such as cyclophosphamide (alkylating agent) and azathioprine (antimetabolites, immunosuppressants) have been used as palliative therapy based on experience.
Further, it is believed that the onset of Alzheimer's disease is triggered by the accumulation of amyloid β peptide (Aβ) in the brain. Therefore, current research and development of drugs for preventing or treating Alzheimer's disease has been conducted with a focus on suppressing the production of Aβ or promoting decomposition of Aβ. It was recently discovered that the decomposition of Aβ can be promoted by inhibiting PAI-1; this finding suggests that a PAI-1 inhibitor may be usable as a drug for treating Alzheimer's disease (Non-Patent Document 27).